rs137852828

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5

The NM_001999.4(FBN2):​c.3425G>T​(p.Cys1142Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FBN2
NM_001999.4 missense

Scores

16
2
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.90
Variant links:
Genes affected
FBN2 (HGNC:3604): (fibrillin 2) The protein encoded by this gene is a component of connective tissue microfibrils and may be involved in elastic fiber assembly. Mutations in this gene cause congenital contractural arachnodactyly. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBN2. . Gene score misZ 1.5491 (greater than the threshold 3.09). Trascript score misZ 3.2752 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, carpal tunnel syndrome, macular degeneration, early-onset, congenital contractural arachnodactyly.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.996
PP5
Variant 5-128338980-C-A is Pathogenic according to our data. Variant chr5-128338980-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 526.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FBN2NM_001999.4 linkuse as main transcriptc.3425G>T p.Cys1142Phe missense_variant 26/65 ENST00000262464.9 NP_001990.2 P35556-1
FBN2XM_017009228.3 linkuse as main transcriptc.3272G>T p.Cys1091Phe missense_variant 25/64 XP_016864717.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FBN2ENST00000262464.9 linkuse as main transcriptc.3425G>T p.Cys1142Phe missense_variant 26/651 NM_001999.4 ENSP00000262464.4 P35556-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251404
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135870
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461814
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727218
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Congenital contractural arachnodactyly Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 01, 2000- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
31
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.96
D;.;D;D
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.96
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
1.0
D;.;.;D
M_CAP
Pathogenic
0.78
D
MetaRNN
Pathogenic
1.0
D;D;D;D
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Pathogenic
4.2
H;.;H;.
PrimateAI
Pathogenic
0.86
D
PROVEAN
Pathogenic
-9.9
D;.;D;D
REVEL
Pathogenic
0.98
Sift
Uncertain
0.0020
D;.;D;D
Sift4G
Pathogenic
0.0
.;.;.;D
Polyphen
1.0
D;.;D;D
Vest4
0.99
MutPred
1.0
Loss of disorder (P = 0.0969);.;Loss of disorder (P = 0.0969);.;
MVP
0.97
MPC
0.86
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.99
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs137852828; hg19: chr5-127674672; API